Disease transmission patterns across different spatial landscapes can be reconstructed using molecular genetic variation to characterize pathogen population structure. Yersinia pestis, causative agent of plague, has impacted humans for thousands of years as it spread locally and globally in major pandemic episodes. As is the case with any recently emerged pathogen, molecular variation for characterizing population structure is rare, which makes population analysis difficult or of poor resolution. We have discovered and developed hypervariable VNTR loci that can be used to determine Y. pestis population structure at multiple spatial scales. We will apply this high-resolution genetic typing system to multiple Y. pestis populations in the western United States and use the resulting information to better understand the biology of this human health threat, model organism, and potential bioterrorism agent. We will genetically characterize the Y. pestis population that was linked to the highly-publicized human cases that were diagnosed in New York City in 2002 and will determine the specific biological components associated with that disease event. In addition, we will genetically characterize multiple epizootic Y. pestis populations from the southwestern United States, including populations on Navajo Nation. Our investigation of multiple plague outbreaks on Navajo Nation and surrounding areas will provide important scientific data that can be used to develop models to predict plague activity in this region, directly addressing one of the objective of NIAID's research program to acquire knowledge that will eventually lead to the prevention of this infectious disease in humans. The results of this study will improve our nation's ability to respond to acts of bioterrorism involving plague by 1) validating the actual assay that would be used to investigate such an attack, 2) populating the genetic database that would be used to pinpoint the source of the strain used in such an attack, and 3) increasing our understanding of VNTR mutation rates that would be used to link the strain to its source. The results of our research will be relevant to public health in several different ways. This widespread effect is due to the fact that plague is 1) a continuing human health threat in some regions of the United States that disproportionately affects Native Americans, 2) a model disease system that can provide insights into more common infectious diseases and future emergent disease threats, and 3) a potential agent of bioterrorism. [unreadable] [unreadable] [unreadable]